Presynaptic Excitation via GABA B Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression

Zhang, Ju-en; Tan, Lubin; Ren, Yuqi; Liang, Jinqian; Lin, Rui; Feng, Qiru; Zhou, Jingfeng; Hu, Fei; Ren, Jing; Wei, Chao; Yu, Tao; Zhuang, Yinghua; Bettler, Bernhard; Wang, Fengchao; Luo, Minmin

doi:10.1016/j.cell.2016.06.026

Cited by 138 publications

(137 citation statements)

References 51 publications

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“…Zhang et al [7] showed that ablation of the vMHb or knocking GABA B receptors out in adult mice increased cue-conditioned fear, which was consistent with our present results. Increased number or function of ErbB4 increased the GABA release, which might lead to repress the excitability of MHb projecting neurons and enhanced contextual-dependent fear memory expression.…”

Section: Discussionsupporting

confidence: 83%

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ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory

et al. 2018

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The Medial Habenular (MHb) and the Lateral Habenular nuclei are 2 main parts of the habenular complex (Hb). Recent studies showed that MHb plays an important role in memory, and in the expression of ErbB4. However, the expression of MHb ErbB4 receptor and its role in fear memory is not well understood. In this study, western blotting and quantitative real-time polymerase chain reaction were used to assess the protein and mRNA levels of ErbB4 in the process of contextual fear conditioning. A pharmacological approach was used to block and stimulate the ErbB4 receptor. Contextual fear conditioning tests induced a significant increase on the expression of ErbB4 at various times in the Hb and the MHb. Moreover, the blockade and stimulation of MHb ErbB4 receptors did not affect the fear formation but impaired and improved the contextual-dependent fear expression. Furthermore, in vitro electrophysiological recordings showed that the blockade of the MHb ErbB4 receptor reduced the presynaptic gamma-amino butyric acid release. ErbB4 is a susceptible gene for schizophrenia and the above findings may provide new insights into the mechanisms of fear-related responses.

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Section: Discussionsupporting

confidence: 83%

“…The Hb has many functions, but some of these remain to be investigated [1,2]. A few studies have reported that the MHb plays a critical role in stress [3,4], depression [5], memory [6,7], and nicotine withdrawal [8].…”

Section: Introductionmentioning

confidence: 99%

ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory

et al. 2018

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“…It is unclear whether the high expression of GABA B receptors in the MHb plays a role in suppression of excitability and the reduction of GABA A receptor mediated currents (Jones et al, 1998; Lüscher et al, 1997; Luscher and Slesinger, 2010; Takeda et al, 2004). Interestingly, a recent study suggested that the GABA B receptors on MHb terminals play a unique excitatory role to enhance neurotransmitter release in the IPN and its activation is critical for fear extinction (Zhang et al, 2016). Therefore, it is plausible that the suppression of the MHb activity by aversive experiences might result in reduced MHb-IPN transmission and hence impair extinction of aversive memories.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the MHb is one of the brain areas that express the highest level of GABA B receptors (Jones et al, 1998). A recent study reported that GABA B receptors on the MHb axon terminals play an excitatory role by promoting neurotransmitter release as they are coupled to presynaptic Ca 2+ -channels (Zhang et al, 2016). These studies suggest a unique role for GABA receptors in MHb function.…”

Section: Introductionmentioning

confidence: 99%

Development- and experience-dependent plasticity in the dorsomedial habenula

Koppensteiner

Galvin

2016

Molecular and Cellular Neuroscience

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Of the two major subdivisions of the habenula, the medial and lateral nuclei, the medial habenula is the least understood in terms of synaptic transmission, intrinsic properties and plasticity. The medial habenula (MHb) is composed of glutamatergic neurons which receive the majority of their inputs from the septal region and project predominantly to the interpeduncular nucleus (IPN). To understand the synaptic transmission, we studied both glutamatergic and GABAergic synaptic transmission in the dorsal region of the medial habenula (dMHb). While glutamatergic transmission dominates during early development, an attenuation of glutamatergic transmission and an enhancement of GABAergic transmission occur during development leading into adulthood. Furthermore, as reported previously, GABAA receptor-mediated transmission is excitatory in the adult dMHb, which is consistent with the reduced expression of the K-Cl co-transporter KCC2. Given the potential role of the dMHb in aversive behaviors, we examined whether fear conditioning or exposure to foot shock affects excitability in dMHb neurons. We observed a suppression of the excitability of dMHb neurons in mice that either underwent fear conditioning or were exposed to foot shock. Furthermore, we observed a suppression of GABAergic but not glutamatergic transmission in the dMHb neurons following fear conditioning. These results suggest that aversive experience produces a suppression of the dMHb neuronal activity. Given that the medial habenula is upstream of the median raphe nucleus which is believed to be involved in the negative regulation of aversive memory, the suppression of dMHb neurons following an aversive experience might play a role in strengthening of aversive memories.

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“…As a result, the habenular complex is frequently described as an "antireward" system, responsible for anxiety-like, aversion and fear behaviors. Recent work has shed light on how the MHb may regulate these behaviors, suggesting that the MHb has a more complex role in regulating fear, learned helplessness and adaptive behaviors (Lee et al 2010;Zhang et al 2016). More specifically, the MHb may play a larger role in adaptive behaviors, where mounting evidence has demonstrated that loss of vMHb function leads to deficits in fear extinction and escape behaviors.…”

Section: Introductionmentioning

confidence: 99%

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

et al. 2018

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Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.

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Presynaptic Excitation via GABA B Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression

Cited by 138 publications

References 51 publications

ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory

ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory

Development- and experience-dependent plasticity in the dorsomedial habenula

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

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